NF-κB is a protein family involved in the regulation of inflammatory response, immune modulation, apoptosis, cell proliferation, epithelial differentiation, and the like. It regulates the expression of various genes and forms the central axis of the intracellular signaling system. NF-κB increases important substances related to cell proliferation, apoptosis, and cell cycle as well as signaling substances of inflammation and immune response. Such disorder of regulation of NF-κB activation pathway causes continuous increase of these mediators, and the condition becomes similar to autoimmune diseases. In addition, NF-κB plays an important role in maintaining oncogenic phenotype by participating in regulation of genes involved in cell proliferation, survival-related genes and angiogenesis, and metastasis. In fact, the sustained expression of NF-κB plays an important role in tumorigenesis and therapy, given that increased NF-κB activity after chemotherapy induces apoptosis suppression and reduces the therapeutic effect of anticancer drugs. It has been revealed that the activity of NF-κB is increased in epithelial cell carcinoma, carcinoma cell line, lymphoma and the like, which means that apoptosis is inhibited and cell proliferation rate and metastasis can be increased. It is known that NF-κB-activated tumors do not respond well to anticancer drugs. As a cause, P-glycoprotein, which causes multidrug resistance, is thought to be the genes regulated by NF-κB. In contrast, inhibition of NF-κB activation in fibrosarcoma, colorectal cancer, and rectal cancer cell lines resulted in a favorable outcome for radiation therapy or chemotherapy treatment by creating an environment where apoptosis is likely to occur easily.
Activation of NF-κB proliferates blood vessels via vascular endothelial growth factor (VEGF), COX-2 and iNOS, and is involved in tumor invasion and metastasis through matrix metalloproteinase, plasminogen activator, heparinase (Heparinase), and the like.
On the other hand, together with NF-κB, STAT3 is also an important transcription factor associated with inflammatory and immune responses. STAT3 (signal transducer and activator of transcription3) is a protein in the cytoplasm that is not activated. It binds to the DNA sequence as part of a group called ‘DNA binding factor’, and regulates the transcription process of transferring genetic information from DNA to RNA. Activation of STAT3 is accomplished by phosphorylation of tyrosine residues in the STAT3 transactivation domain by a variety of growth factors and cytokines. This phosphorylated STAT3 (p-STAT3) enters the nucleus and induces the expression of a wide range of target genes involved in inflammatory responses and tumorigenesis. In addition to the association with STAT3 and arthritis, STAT3 also affects the mechanism of cancer development and treatment. STAT3 is the only molecule that regulates the genes involved in the initiation and promotion of cancer. STAT3 acts as the first step in cancer development progress stage. In addition, the STAT3 is a transcription factor protein. The role of STAT3 is a signal transduction activation factor that leads to cancer by inadequately sending an external signal to differentiate healthy cells, in addition to wound treatment, which is associated with tumorigenesis. Yu H. et al. indicate that sustained activation of STAT3 mediates inflammatory responses that promote tumors, while STAT3, which is activated at all times, and some STAT5 increase tumor cell proliferation, survival and invasion while inhibiting anti-tumor immune action. That is, a transient inflammatory signal can activate an epigenetic switch that converts unmodified cells into cancer cells through a positive feedback loop such as NF-κB, Lin28, Let-7, and IL-6. At this time, STAT3 transcription factor activated by the IL-6 directly activates microRNAs such as miR-21 and miR-181b-1, which inhibit PTEN (phosphatase and tensin homolog) and CYLD (cylindromatosis) tumor suppressor, and induces NF-κB activation increase.
That is, STAT3 is a part of the positive feedback loop that is the basis of the epigenetic switch that links inflammation to cancer with the cytokines such as miR-21, miR-181b-1, PTEN and CYLD.
In addition, STAT3 is always activated in a wide range of tumors, including colorectal cancer, colon cancer, liver cancer, breast cancer, prostate cancer, multiple myeloma, and glioblastoma. This is because tumor cells depend on STAT3 to sustain growth and avoid apoptosis.
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